1. Field
The present disclosure relates to a pharmaceutical composition for preventing or treating cancer, and more particularly, to a pharmaceutical composition for preventing or treating cancer that includes dendritic cells with a knock-down disabled 2 (Dab2) gene.
2. Discussion of Related Art
Dendritic cells (DCs) are antigen-presenting cells (APCs) which play a critical role in the initiation of an antigen-specific adaptive immune response. DCs have various characteristics according to their origin, phenotype, function, and maturation process. Generally, to be used in DC studies, DCs are prepared by extracting mouse bone marrow stem cells or human monocytes and differentiating the stem cells or monocytes in media, to which granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4 are added in vitro. However, an in vivo mechanism for differentiation of bone marrow stem cells into DC, and their maintenance, is little known. Environmental or genetic factors are also critical factors in DC differentiation, but are not known so far. DCs may be critical in stimulating or suppressing a T cell response depending on the situation, thereby regulating in vivo immune homeostasis. Locally, immune tolerance DCs are involved in an immune inhibition or immune tolerance mechanism through activation of regulatory T cells (Treg cells), and thus a cytokine such as interleukin 10 (IL-10) or a transforming growth factor-β (TGF-β) may be expressed, resulting in immune regulation. Treg cells expressing TGF-β and Foxp3 serve to regulate immune responses, and play important roles in maintaining immune homeostasis.
Meanwhile, a Dab2 gene is well known as an adaptor protein involved in a signal transduction mechanism and endocytosis using several receptors. A Dab2 protein has a phosphotyrosine-binding domain binding to membrane proteins such as a low density lipoprotein receptor (LDL receptor) and a TGF-β receptor at the N-terminus. In addition, Dab2 includes a proline-rich domain (PRD) capable of binding to a protein having an SH3 domain such as Grb2 at the C-terminus. The Dab2 gene expresses two types of proteins including P96 and P67. While the main type, the P96 Dab2 protein, is expressed in adults, the P67 protein is generally expressed during embryonic development.
The Dab2 protein is expressed in cells of various tissues or organs including brain, kidney, ovary, and breast. Dab2 shows a lower expression in several tumor tissues than normal tissue, and in normal cells, Dab2 expression strongly suppresses cell proliferation. Thus, the Dab2 protein is known as a critical tumor suppressor. A mitogen-activated protein kinase (MAPK) signal transduction (Ras-Raf pathway) mechanism is critically useful in cell growth, proliferation, and differentiation. Dab2 competitively binds to Grb2 regulating a growth factor and a Ras pathway with Sos. The tumor suppression mechanism of Dab2 is known to suppress formation of cancer by Wnt in the manner of interrupting an endocytosis mechanism of low-density lipoprotein receptor-related protein 6 (LRP6) through Wnt/β-catenin signal transduction, in which Wnt binds to LRP6 phosphorylated at a S1579 site by a casein kinase 2 (CK2). However, such a tumor suppression mechanism of Dab2 cannot explain regulation of the Wnt/β-catenin signal transduction mechanism essentially involved in thymus differentiation or T cell differentiation, survival, and maturation.
Meanwhile, most known cancer treatments mainly include surgery, anticancer agents, and radiotherapy. However, these treatments are accompanied by, for example, side effects, difficulty in attaining a full recovery, and therefore may not be an optimal fundamental treating method of cancer. Particularly, in the case of metastatic cancer or recurrent cancer, in most cases, it is impossible to apply a surgical treatment. And there is a resistance to a chemotherapeutic agent in many cases. Therefore development of a new treating agent for these cancer patients is eagerly sought. Meanwhile, a recently developed cancer treating agent using DCs (refer to Korean Patent No. 10-1169331), compared to conventional agents, exhibits long-term efficacy due to immunological memory, is very effective and safe in prevention of metastasis or reoccurrence of the same cancer, and thus is expected to be a new anticancer immunotherapy. However, for the last decade, efficacy of a DC vaccine for treating cancer did not show an expected effect, and thus the disclosure of the present application is directed to an increase in efficacy of a DC vaccine.